Hepatic steatosis or “fatty liver” is the accumulation of fat in the liver. Non-alcoholic fatty liver disease (NAFLD) requires that there is evidence of hepatic steatosis, either by histology or imaging, and there are no causes for secondary fat accumulation, such as significant alcohol consumption, use of steatogenic drugs, or hereditary disorder. NAFLD can be diagnosed by liver biopsy, ultrasonography, or, more recently, by magnetic resonance spectroscopy (MRS) or magnetic resonance imaging. (MRI). MRS and MRI are now regarded as the most accurate practical methods of measuring liver fat in clinical practice. Patients with NAFLD, i.e., simple steatosis or fatty liver, are thought to have benign prognoses with no evidence of increased mortality (Kim et al., Hepatology, 2013, 57:1357-1365; Sanyal et al., Gastroenterology, 2016, 150: 11-13).
Separate from NAFLD, non-alcoholic steatohepatitis (NASH) is a non-benign disorder characterized by substantial health risks. In addition to having excess fat in the liver, NASH is characterized by histologic evidence of hepatic inflammation and hepatocyte injury (ballooning), with or without fibrosis. NASH is characterized by increased risk of cardiovascular and liver-related mortality. NASH can lead to cirrhosis, in which the liver is permanently damaged and scarred. Cirrhosis results in fluid retention, muscle wasting, bleeding from the intestines, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure. Transplantation is increasingly performed in people with NASH. NASH is currently the number two reason for liver transplants, and it will very likely be number one by the end of the decade as new antiviral drugs control hepatitis C, which is presently the number one cause of liver failure.
NASH is typically diagnosed by liver biopsy and is based on histological evidence of steatosis, inflammation, and hepatocyte ballooning in the absence of other causes of liver disease or substantial alcohol consumption. The NAFLD Activity Score (NAS) was developed to provide a numerical score for patients who most likely have NASH. NAS is the sum of separate scores for steatosis (0-3), hepatocellular ballooning (0-2), and lobular inflammation (0-3), with a maximal score of 8. A score of ≥5 suggests probable NASH, and <3 indicates that NASH is unlikely. See, Kleiner et al, “Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease, Hepatology”, 41(6):1313-1321 (2005).
Although liver biopsy remains the gold standard for characterizing liver histology and diagnosing NASH, it is expensive and carries some morbidity and very rare mortality. Consequently, there is much interest in the development of non-invasive surrogate markers for the diagnosis of NASH, as well as the use of these markers to monitor the efficacy of experimental drugs in NASH clinical trials.
Currently, there is no USFDA-approved drug for the treatment of NASH. In 2009 the American Association for the Study of Liver Disease (AASLD) held a workshop on clinical trial design and end points for assessing treatment of NASH. Two histologic end points were proposed: 1) Resolution of steatohepatitis without worsening of fibrosis, and 2) at least a two-point improvement in NAS without worsening of fibrosis (Sanyal, A J, et al., Hepatology, 2011, 54:344-353).
There have been several randomized clinical trials using histology as the primary end point. In the Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis (PIVENS) trial, histologic response was determined by improvement in the ballooning score by ≥1 point; no increase in fibrosis; either a decrease in the NAS score to ≤3 or a decrease in the score of at least 2 points, with a 1 point decrease in lobular inflammation or steatosis score (Sanyal et al., NEJM, 2010, 362: 1675-1685). Vitamin E treatment produced a significant histologic improvement compared with placebo according to the above criteria, whereas the improvement with pioglitazone compared to placebo was not significant (p=0.04, with 0.025 considered statistically significant). However, both drugs are associated with significant side effects: an increased risk of prostate cancer with vitamin E and weight gain and increased risk of heart failure and fractures with pioglitazone.
The two experimental agents most advanced in clinical trials for the treatment of NASH are GFT 505, a dual PPAR α/δ agonist, and obeticholic acid (OCA), a farnesoid X nuclear receptor ligand. In a one-year phase 2 trial in NASH patients, an oral dose of 150 mg GFT 505 failed to produce a statistically significant improvement in histologically-assessed NASH vs. placebo. However, the drug did show a statistically significant improvement vs. placebo when patients with the mildest form of NASH (NAS<3) were excluded from analysis.
In a phase 2 trial (FLINT), obeticholic acid (25 mg) or placebo was administered to NASH patients for 72 weeks, with the primary outcome of a centrally scored liver histology, defined as a decrease in the NAS score of at least 2 points without worsening of fibrosis. Forty-five percent of obeticholic acid-treated patients achieved the primary end point vs. 23% of the placebo (p=0.002). However, despite these improvements in individual histological features, the proportion of patients with resolution of NASH, as determined from a baseline diagnosis to a non-NASH diagnosis, did not differ in patients treated with drug vs. placebo. The overall degree of histological improvement was similar to that seen with vitamin E and pioglitazone in the PIVENS Trial, although the two studies had somewhat different inclusion and exclusion criteria and primary end points.
Obeticholic acid treatment also produced a significant increase in plasma LDL and total cholesterol, as well as a decrease in insulin sensitivity, all of which could presage an increase in cardiovascular risk. Excess mortality in subjects with NASH is related to liver-related deaths, cardiovascular disease, and non-hepatocellular cancers. An ideal treatment for NASH should be one that improves not only liver disease, but also reduces the risks of cardiovascular outcomes and development of diabetes and cancers (Sanyal et al., Hepatology, 2011, 54: 344-353). Obviously, a drug that favorably impacts these various non-liver related indications, in addition to improving the liver disease per se, would be an attractive treatment for NASH.